Bicyclic amine derivatives

ABSTRACT

A compound of formula (I): ##STR1## wherein Ar is optionally substituted phenyl or optionally substituted 5-or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms individually selected from nitrogen, oxygen and sulfur atoms, and at least one unsaturation (double bond) between adjacent atoms in the ring, said heterocyclic ring being optionally fused to a benzene ring; or an acid addition salt, quaternary ammonium salt or N-oxide derived therefrom, an insecticidal, acaricidal or nematicidal composition comprising a compound of formula (I) and a suitable carrier or diluent therefor, a method of combating and controlling insect, acarine or nematode pests at a locus which comprises treating the pests or the locus of the pests with an effective amount of a compound of formula (I) or a composition as hereinbefore described.

This invention relates to novel bicyclic amine derivatives, to processesfor preparing them, to insecticidal compositions comprising and tomethods of using them to combat and control insect pests.

The invention provides a compound of formula (I): ##STR2## wherein Ar isoptionally substituted phenyl or optionally substituted 5-or 6-memberedheterocyclic ring containing from 1 to 3 heteroatoms individuallyselected from nitrogen, oxygen and sulfur atoms, and at least oneunsaturation (double bond) between adjacent atoms in the ring, saidheterocyclic ring being optionally fused to a benzene ring, wherein thesubstutuents, if present, are selected from halogen atoms, cyano, alkyl,alkenyl, alkynyl, alkoxy, haloalkyl, haloalkenyl, alkylthio and alkylamino groups; R represents hydrogen or cyano or a group selected fromalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl,alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl,alkenyloxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl,heterocyclylalkyl, carbamyl, dithiocarboxyl or XR³ (where X representsoxygen or a group NR⁴), provided that when R is alkenyl, aralkenyl oralkynyl said goup does not have an unsaturated carbon atom bondingdirectly to the ring nitrogen of formula (I); R³ and R⁴ are,independently, hydrogen, alkyl, aryl, heteroaryl, aralkyl,heteroarylalkyl, alkenyl, aralkenyl, alkynyl, heterocyclylalkyl,alkoxycarbonyl or carboxylic acyl; alkyl moieties of R, R³ and R⁴comprise from 1 to 15 carbon atoms, and are optionally substituted withone or more substituents selected from halogen, cyano, carboxyl,carboxylic acyl, carbamyl, alkoxycarbonyl, alkoxy, alkylenedioxy,hydroxy, nitro, amino, acylamino, imidate and phosphonato groups; aryl,heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl,alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkanyloxycarbonyl,aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl ordithiocarboxyl moieties of R, R³ and R⁴ comprise from 1 to 15 carbonatoms, and are optionally substituted with one or more substituentsselected from, halogen, cyano, carboxyl, carboxylic acyl, carbamyl,alkoxycarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl,amino, acylamino, imidate and phosphonato groups; R¹ representshydrogen, hydroxy, alkyl, alkoxy, amino, nitro, isocyanato, acylamino,hydroxyalkyl, optionally substituted heteroaryl, alkoxyalkyl, haloalkyl,halohydroxyalkyl, aralkyloxyalkyl, acyloxyalkyl, amidoximido,sulfonyloxyalkyl, aminoalkyl, alkoxycarbonylamino, acylaminoalkyl,cyanoalkyl, imino, formyl, acyl or carboxylic acid or an ester or amidethereof, or alkenyl or alkynyl either of which is optionally substitutedby halogen, alkoxy, cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl or cyano; or an acid addition salt, quaternaryammonium salt or N-oxide derived therefrom.

It will be appreciated that the bicyclic amine compounds of formula (I)are capable of existing in more than one isomeric form since the groupsAr and R¹ may be positioned in either an exo or endo relationship, andthe present invention embraces within its scope both exo and endo formsand mixtures thereof in all proportions and also any further isomericvariants arising from cis and trans substitution patterns or chiralcentres present in either of Ar, R or R¹.

Examples of 5- and 6-membered heterocyclic ring systems represented byAr include those based on pyridine, pyrazine, pyridazine, pirimidine,pyrrole, pyrazole, imidazole, 1,2,3- and 1,2,4-triazoles, furan,thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,2,3- and1,3,4-oxadiazoles, and 1,2,3- and 1,3,4-thiadiazoles, and partiallyreduced containing one double bond derived from these, as well as thosebased on oxathiole, dioxole, and dithiole rings containing one doublebond. Preferably Ar represents a halo-substituted phenyl, pyridyl ordiazinyl group.

When Ar is a 5- or 6- membered hererocyclic ring fused to a benzene ringthen it is preferably benzoxazole, indole, benzofuran, benzothiophen orbenzimidazole.

Halogen includes fluorine, chlorine, bromine and iodine.

Alkyl moieties preferably contain from 1 to 6, more preferably from 1 to4, carbon atoms. They can be in the form of straight or branched chains,for example methyl, ethyl, n- or iso-propyl, or n-, sec-, iso- ortert-butyl.

Haloalkyl is preferably C₁₋₆ haloalkyl, especially fluoroalkyl (forexample trifluoromethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl) orchloroalkyl. For R, haloalkyl is preferably C₂₋₆ haloalkyl wherein thereis no halogen on the α-carbon (for example 2,2,2-trifluoroethyl or2,2-difluoroethyl).

Alkenyl and alkynyl moieties of R¹ and substituents of Ar preferablycontain from 2 to 6, more preferably from 2 to 4, carbon atoms. They canbe in the form of straight or branched chains, and, where appropriate,the alkenyl moieties can be of either (E)- or (Z)-configuration.Examples are vinyl, allyl and propargyl.

Aryl includes naphthyl but is preferably phenyl.

Heteroaryl includes 5- and 6-membered aromatic rings containing one,two, three or four heteroatoms selected from the list comprising oxygen,sulphur and nitrogen and can be fused to benzenoid ring systems.Examples of heteroaryl are pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl (1,2,3- and 1,2,4-),tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,quinoxalinyl, indolinyl, isoindolinyl, benzofuranyl, benzothienyl andbenzimidazolinyl.

The heterocyclyl part of heterocyclylalkyl is a ring containing one ortwo heteroatoms selected from the list comprising oxygen, sulphur andnitrogen. Examples are piperidine, piperazine, pyrrolidine,tetrahydrofuran, morpholine, thietane, pyridine or thiazole.

The alkylenedioxy group is a substituent for a ring and is especiallyC₁₋₄ alkylenedioxy. Alkylenedioxy groups are optionally substituted withhalogen (especially flourine) and are, for example, methylenedioxy (OCH₂O) or difluoromethylenedioxy (OCF₂ O).

Suitable acid addition salts include those with an inorganic acid suchas hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, oran organic carboxylic acid such as oxalic, tartaric, lactic, butyric,toluic, hexanoic and phthalic acids, or sulphonic acids such as methane,benzene and toluene sulphonic acids. Other examples of organiccarboxylic acids include haloacids such as trifluoroacetic acid.

In one particular aspect the present invention provides a compound offormula (I), wherein Ar is optionally substituted phenyl or optionallysubstituted 5-or 6-membered heterocyclic ring containing from 1 to 3heteroatoms individually selected from nitrogen, oxygen and sulfuratoms, and at least one unsaturation (double bond) between adjacentatoms in the ring, said heterocyclic ring being optionally fused to abenzene ring, wherein the substutuents, if present, are selected fromhalogen atoms, cyano, alkyl (especially C₁₋₄ alkyl), alkenyl (especiallyC₂₋₄ alkenyl), alkynyl (especially C₂₋₄ alkynyl), alkoxy (especiallyC₁₋₄ alkoxy), haloalkyl (especially C₁₋₄ haloalkyl), haloalkenyl(especially C₂₋₄ haloalkenyl), alkylthio (especially C₁₋₄ alkylthio),and alkyl amino (especially mono- or di- (C₁₋₄ alkyl)amino, such asmono- or di- (C₁₋₃ alkyl)amino) groups; R represents hydrogen or cyanoor a group selected from alkyl (especially C₁₋₄ alkyl), aryl (especiallyphenyl), heteroaryl (especially pyridinyl or pyrimidinyl), aralkyl(especially aryl(C₁₋₄)alkyl, such as phenyl(C₁₋₄) alkyl),heteroarylalkyl (especially heteroaryl(C₁₋₄)alkyl, such aspyridinyl(C₁₋₄)alkyl or pyrimidinyl(C₁₋₄)alkyl), alkenyl (especiallyC₃₋₄ alkenyl), aralkenyl (especially aryl(C₃₋₄)alkenyl, such asphenyl(C₃₋₄)alkenyl), alkynyl (especially C₃₋₄ alkynyl), alkoxycarbonyl(especially C₁₋₄ alkoxycarbonyl), alkanesulfonyl (especially C₁₋₄alkylsulfonyl), arenesulfonyl (especially phenylsulfonyl),alkenyloxycarbonyl (especially C₃₋₄ alkenyloxycarbonyl),aralkyloxycarbonyl (especially phenyl(C₁₋₄)alkoxycarbonyl),aryloxycarbonyl (especially phenoxycarbonyl), heterocyclylalkyl(especially heterocyclyl(C₁₋₄)alkyl, such as piperidinyl(C₁₋₄)alkyl),carbamyl (H₂ NC(O)), dithiocarboxyl or XR³ (where X represents oxygen ora group NR⁴), provided that when R is alkenyl, aralkenyl or alkynyl saidgoup does not have an unsaturated carbon atom bonding directly to thering nitrogen of formula (I); R³ and R⁴ are, independently, hydrogen,alkyl (especially C₁₋₄ alkyl), aryl (especially phenyl), heteroaryl(especially pyridinyl or pyrimidinyl), aralkyl (especiallyaryl(C₁₋₄)alkyl, such as phenyl(C₁₋₄)alkyl), heteroarylalkyl (especiallyheteroaryl(C₁₋₄)alkyl, such as pyridinyl(C₁₋₄)alkyl orpyrimidinyl(C₁₋₄)alkyl), alkenyl (especially C₂₋₄ alkenyl), aralkenyl(especially aryl(C₂₋₄)alkenyl, such as phenyl(C₂₋₄)alkenyl), alkynyl(especially C₂₋₄ alkynyl), heterocyclylalkyl (especiallyheterocyclyl(C₁₋₄)alkyl, such as piperidinyl(C₁₋₄ )alkyl),alkoxycarbonyl (especially C₁₋₄ alkoxycarbonyl) or carboxylic acyl(especially C₁₋₄ alkylcarbonyloxy); alkyl moieties of R, R³ and R⁴comprise from 1 to 15 carbon atoms, and are optionally substituted withone or more substituents selected from halogen, cyano, carboxyl(HOC(O)), carboxylic acyl (especially C₁₋₄ alkylcarbonyloxy), carbamyl(H₂ NC(O)), alkoxycarbonyl (especially C₁₋₄ alkoxycarbonyl), alkoxy(especially C₁₋₄ alkoxy), alkylenedioxy (especially C₁₋₄ alkylenedioxy),hydroxy, nitro, amino, acylamino (especially C₁₋₄ alkylcarbonylamino),imidate (C₁₋₄ alkyl[C(O)NHC(O)]) and phosphonato (OP(OH)₂) groups; aryl,heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl,alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkenyloxycarbonyl,aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl,dithiocarboxyl moieties of R, R³ and R⁴ comprise from 1 to 15 carbonatoms, and are optionally substituted with one or more substituentsselected from, halogen, cyano, carboxyl (HOC(O)), carboxylic acyl(especially C₁₋₄ alkylcarbonyloxy), carbamyl (H₂ NC(O)), alkoxycarbonyl(especially C₁₋₄ alkoxycarbonyl), alkoxy (especially C₁₋₄ alkoxy),alkylenedioxy (especially C₁₋₄ alkylenedioxy), hydroxy, nitro, haloalkyl(especially C₁₋₄ haloalkyl), alkyl (especially C₁₋₄ alkyl), amino,acylamino (especially C₁₋₄ alkylcarbonylamino), imidate (C₁₋₄alkyl[C(O)NHC(O)]) and phosphonato (OP(OH)) groups; R¹ is hydrogen,hydroxy, alkyl (especially C₁₋₄ allyl), alkoxy (especially C₁₋₄ alkoxy),amino (especially unsubstituted, mono- or di-(C₁₋₄)alkylamino or aminosubstituted with a formyl group), nitro, isocyanato, acylamino(especially C₁₋₄ alkylcarbonylamino or phenylcarbonylamino),hydroxyalkyl (especially monohydroxy(C₁₋₄)alkyl), optionally substitutedheteroaryl (especially tetrazole, oxadiazole, pyridinyl or pyrimidinyloptionally substituted by halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy or C₁₋₄ haloalkoxy), alkoxyalkyl (especially C₁₋₄alkoxy(C₁₋₄)alkyl), haloalkyl (especially C₁₋₄ haloalkyl),halohydroxyalkyl (especially C₁₋₄ halohydroxyalkyl, such as2-hydroxy-1,1-difluoroethyl), aralkyloxyalkyl (especiallyphenyl(C₁₋₄)alkoxy(C₁₋₄)alkyl), acyloxyalkyl (especially C₁₋₄alkylcarbonyloxy(C₁₋₄ alkyl), amidoximido (C(NH₂)NOH), sulfonyloxyalkyl(especially sulfonyloxy(C₁₋₄)alkyl), aminoalkyl (especiallyamino(C₁₋₄)alkyl), alkoxycarbonylamino (especially C₁₋₄alkoxycarbonylamino), acylaminoalkyl (especially C₁₋₄alkylcarbonylamino(C₁₋₄)alkyl or phenylcarbonylamino(C₁₋₄)alkyl),cyanoalkyl (especially C₁₋₄ cyanoalkyl), imino (especially hydroxyimino(HON═CH) or C₁₋₄ alkoxyimino), formyl, acyl (especially C₁₋₄alkylcarbonyl) or carboxylic acid or an ester (especially a C₁₋₄ alkylester) or amide (especially an unsubstituted or an N,N-di(C₁₋₄)alkylamide) thereof, or alkenyl (especially C₂₋₄ alkenyl) or alkynyl(especially C₂₋₄ alkynyl) either of which is optionally substituted byhalogen, alkoxy (especially C₁₋₄ alkoxy), cycloalkyl (especially C₃₋₇cycloalkyl, such as cyclopropyl or cyclohexyl), optionally substitutedaryl (especially phenyl optionally substituted by halogen, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy), optionally substitutedheteroaryl (especially pyridinyl or pyrimidinyl optionally substitutedby halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy)or cyano; or an acid addition salt, quaternary ammonium salt or N-oxidederived therefrom.

In a further aspect the present invention provides a compound of formula(Ia): ##STR3## wherein A represents dimethylene; Ar represents anoptionally substituted phenyl or 5-or 6-membered heterocyclic ringsystem containing from 1 to 3 heteroatoms individually selected fromnitrogen, oxygen and sulfur atoms, and at least one unsaturation (doublebond) between adjacent atoms in the ring, wherein the substutuents, ifpresent, are selected from halogen atoms, alkyl, alkenyl, alkynyl,alkoxy, haloalkyl, haloalkenyl, alkylthio and alkyl amino groups, any ofwhich groups contain up to six carbon, and wherein R represents hydrogenor cyano or a group selected from alkyl, aryl, heteroaryl, aralkyl,heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl,alkanesulfonyl, arenesulfonyl, alkanyloxycarbonyl, aralkyloxycarbonyl,aryloxycarbonyl, heterocyclylalkyl, carbamyl or dithiocarboxyl groups,said groups comprising from 1 to 15 carbon atoms, said groups beingoptionally substituted with one or more substituents selected from,halogen, cyano, carboxyl, carboxylic acyl, carbamyl, alkoxycarbonyl,alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl, amino,acylamino, imidate and phosphonato groups; R¹ represents hydroxy, or agroup selected from alkoxy, amino, acylamino, hydroxyalkyl, alkoxyalkyl,haloalkyl, halohydroxyalkyl, aralkyloxyalkyl, acyloxyalkyl,sulfonyloxyalkyl, aminoalkyl, acylaminoalkyl, cyanoalkyl, formyl, acyl,carboxylic acid and esters and amides thereof, alkenyl or alkynyloptionally substituted by halogen, alkoxy, aryl, heteroaryl or cyano;and acid addition salts and quaternary ammonium salts and N-oxidesderived therefrom.

In a still further aspect the present invention provides a compound offormula (I), wherein Ar is pyridinyl (especially a pyridin-3-yl)optionally substituted by halogen (especially monosubstituted withchlorine or bromine), or phenyl optionally substituted by halogen(especially fluorine).

In another aspect the present invention provides a compound of formula(I), wherein Ar is phenyl, pyridinyl, pyridazinyl or pyrazinyl, allbeing optionally substituted with halogen (especially fluorine, chlorineor bromine), C₁₋₄ alkyl (especially methyl), C₁₋₄ alkoxy (especiallymethoxy), C₂₋₄ alkenyl, C₂₋₄ alkynyl or cyano.

In a further aspect the present invention provides a compound of formula(I) wherein R is C₁₋₄ alkyl (optionally substituted with cyano, CO₂(C₁₋₄ alkyl) or phenyl (itself optionally substituted with halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl or C₁₋₄ haloalkoxy)), C₂₋₄ haloalkyl(the α-carbon being unsubstituted), C₃₋₄ alkenyl or C₃₋₄ alkynyl;provided that when R is alkenyl or alkynyl said goup does not have anunsaturated carbon atom bonding directly to the ring nitrogen of formula(I).

In yet another aspect the present invention provides a compound offormula (I), wherein R is C₁₋₄ alkyl (especially methyl), C₂₋₄ haloalkyl(the a-carbon being unsubstituted, especially C₂₋₄ fluoroalkyl, forexample CH₂ CF₃ or CH₂ CF₂ H) or C₁₋₄ alkoxycarbonyl (such as CH₃ CH₂OC(O) or (CH₃)₃ COC(O)).

In a further aspect the present invention provides a compound of formula(I), wherein R¹ is alkyl (especially C₁₋₄ alkyl), amino (especiallymono- or di-(C₁₋₄)alkylamino), nitro, isocyanato, hydroxyalkyl(especially monohydroxy(C₁₋₄)alkyl), alkoxyalkyl (especially C₁₋₄alkoxy(C₁₋₄)alkyl), haloalkyl (especially C₁₋₄ haloalkyl),halohydroxyalkyl (especially C₁₋₄ halohydroxyalkyl, such as2-hydroxy-1,1-difluoroethyl), aralkyloxyalkyl (especiallyphenyl(C₁₋₄)alkoxy(C₁₋₄)alkyl), acyloxyalkyl (especially C₁₋₄alkylcarbonyloxy(C₁₋₄)alkyl), alkoxycarbonylamino (especially C₁₋₄alkoxycarbonylamino), acylaminoalkyl (especially C₁₋₄alkylcarbonylamino(C₁₋₄)alkyl or phenylcarbonylamino(C₁₋₄)alkyl),cyanoalkyl (especially C₁₋₄ cyanoalkyl), acyl (especially C₁₋₄alkylcarbonyl) or carboxylic acid or an ester (especially a C₂₋₄ alkylester) thereof, or alkenyl (especially C₂₋₄ alkenyl) or alkynyl(especially C₂₋₄ alkynyl) either of which is optionally substituted byhalogen, alkoxy (especially C₁₋₄ alkoxy), cycloalkyl (especially C₃₋₇cycloalkyl, such as cyclopropyl or cyclohexyl), optionally substitutedaryl (especially phenyl optionally substituted by halogen, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy), optionally substitutedheteroaryl (especially pyridinyl or pyrimidinyl optionally substitutedby halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy)or cyano.

In a still further aspect the present invention provides a compound offormula (I), wherein R¹ is C₂₋₄ alkenyl (especially vinyl) or C₂₋₄alkynyl (especially ethynyl) either of which is optionally substitutedby halogen, alkoxy (especially C₁₋₄ alkoxy), cycloalkyl (especially C₃₋₇cycloalkyl, such as cyclopropyl or cyclohexyl), phenyl (optionallysubstituted by halogen), pyridinyl (optionally substituted by halogen)or cyano.

Specific compounds of formula (I) are presented in Table I below.

                                      TABLE I                                     __________________________________________________________________________    Compound                                                                        No. Ar R R.sup.1                                                            __________________________________________________________________________    1     5-Cl-pyridin-3-yl                                                                        CH.sub.2 CF.sub.3                                                                     CH(O)                                                  2 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CCl.sub.2                        3 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 C.tbd.CH                                4 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH.sub.2 OH                             5 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 C.tbd.CCl                               6 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 H                                       7 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CO.sub.2 H                              8 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CO.sub.2 CH.sub.3                       9 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═NOH                              10 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═NOCH.sub.3                      11 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═C(CN).sub.2                     12 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CHF.sub.2                              13 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CF.sub.3                               14 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CH.sub.2                        15 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CH (cyclopropyl)                16 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CHOCH.sub.3                     17 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CHCl (E)                        18 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CHCl (Z)                        19 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CH(C.sub.6 H.sub.5)                                     20 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH═CH                             CN (E)                                                 21 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH.sub.2 OCH.sub.3                     22 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 C.tbd.C (pyridin-3-yl)                 23 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 C.tbd.C(4-F--C.sub.6 H.sub.4)                                  24 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 C.tbd.C                               (pyridin-2-yl)                                         25 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 CH.sub.2 OC(O)C(CH.sub.3).sub.3                                26 3,5-F.sub.2 --C.sub.6 H.sub.3 CH.sub.3                                    CH.sub.2 NHC(O)CH.sub.3                                27 3,5-F.sub.2 C.sub.6 H.sub.3 CH.sub.3 CH.sub.2 NH.sub.2                     28 3,5-F.sub.2 --C.sub.6 H.sub.3 CH.sub.3 CH.sub.2 NHC(O)(C.sub.6                                    H.sub.5)                                               29 3,5-F.sub.2 --C.sub.6 H.sub.3 CH.sub.3 NHC(O)OCH.sub.3                     30 pyridin-3-yl CH.sub.3 OCH.sub.3                                            31 6-C1-pyridin-3-yl CO.sub.2 C(CH.sub.3).sub.3 OCH.sub.3                     32 6-Cl-pyridin-3-yl CH.sub.3 OCH.sub.3                                       33 pyridin-3-yl CO.sub.2 C(CH.sub.3).sub.3 OCH.sub.3                          34 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 tetrazo-5-yl                           35 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 5-CH.sub.3 -1,2,4-oxadiazol-3-yl       36 5-Cl-pyridin-3-yl CH.sub.2 CF.sub.3 C(NH.sub.2)═NOH                    37 5-Cl-pyridin-3-yl CO.sub.2 CH.sub.2 CH.sub.3 NH.sub.2                      38 5-Cl-pyridin-3-yl CO.sub.2 CH.sub.2 CH.sub.3 CONH.sub.2                    39 5-Cl-pyridin-3-yl CO.sub.2 CH.sub.2 CH.sub.3 NHCHO                         40 5-Cl-pyridin-3-yl CO.sub.2 CH.sub.2 CH.sub.3 .sup.+ N.tbd.C.sup.-                                  41 5-Cl-pyridin-3-yl CO.sub.2 CH.sub.2 CH.sub.3                              NO.sub.2                                               42 5-Cl-pyridin-3-yl-N- CO.sub.2 CH.sub.2 CH.sub.3 NO.sub.2                    oxide                                                                        43 3,5-F.sub.2 --C.sub.6 H.sub.3 CO.sub.2 C(CH.sub.3).sub.3 OH                44 5-Cl-pyridin-3-yl CH.sub.2 CH═CH.sub.2 CH═CH.sub.2                 45 5-CN-pyridin-3-yl CH.sub.2 CH═CH CH═CH.sub.2                       46 5-Br-pyridin-3-yl CH.sub.2 CH.tbd.CCH.sub.3 CH═CH.sub.2                47 5-CH.sub.3 O-pyridin-3-yl CH.sub.2 CHF.sub.2 CH═CH.sub.2                                       48 5-acetylenyl-pyridin-3-yl CH.sub.2 CO.sub.2                               CH.sub.3 CH═CH.sub.2                               49 6-Cl-pyrazin-2-yl CH(CH.sub.3)CO.sub.2 CH.sub.3 CH═CH.sub.2                                    50 6-CH.sub.3 O-pyrazin-2-yl CO.sub.2 CH.sub.3                               CH═CH.sub.2                                        51 5-Cl-pyridin-3-yl CH.sub.2 CN CH═CH.sub.2                              52 5-Cl-pyridin-3-yl CH.sub.2 CH.sub.2 CN CH═CH.sub.2                     53 5-Cl-pyridin-3-yl CH.sub.2 C.sub.6 H.sub.5 CH═CH.sub.2                 54 5-Cl-pyridin-3-yl CH.sub.2 CH.sub.2 CF.sub.3 CH═CH.sub.2                                       55 5-Cl-pyridin-3-yl CH.sub.2 CH(CH.sub.3).sub.2                              CH═CH.sub.2                                       56 5-Cl-pyridin-3-yl H CH═CH.sub.2                                      __________________________________________________________________________

The preparation of the compounds of formula (I) may be accomplished byuse of one or more of the synthetic techniques described below andfurther illustrated in the Examples.

The compounds of formula (I) can be prepared from compounds of formula(II) by reacting the compounds of formula (II) in ways described in theliterature to convert a cyano group to an R¹ group or replace a cyanogroup with an R¹ group.

Compounds of formula (II) can also be prepared by treating compounds offormula (VI) with a suitable base, such as lithium diisopropylamide(LDA), and reacting the product so formed with a halide ArHal, whereinHal is a halogen atom.

Compounds of formula (VI) can be prepared by treating3-cyano-8-azabicyclo[3.2.1]octane (VII) with a suitable base, such aspotassium carbonate, in the presence of a halide RL', wherein L' is aleaving group (especially halogen or triflate).

3-Cyano-8-azabicyclo[3.2.1]octane (VII) can be prepared by demethylating3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) by, for example,treating them with a chloroformate ester (such as vinyl chloroformate)to produce a carbamate, and subjecting the product so formed to acidhydrolysis.

Alternatively, compounds of formula (VI) can be prepared by treatingcompounds of formula (VIII) with tosylmethyl isocyanide in the presenceof a suitable base, such as potassium ethoxide.

Compounds of formula (VIII) can be prepared by the Robinson tropinonesynthesis, see, for instance, J. Chem. Soc., (1917) 111, 762.Alternatively, compounds of formula (VIII) can be prepared by reactingcyclohepta-2,6-dienone (XI) with an amine, RNH₂, as described in, forexample, Tetrahedron, (1973) 155, Bull. Chem. Chem. Soc. Jpn., (1971)44, 1708 or J. Org. Chem., (1971) 36, 1718.

The compounds of formula (I) wherein R is methyl, can be prepared fromcompounds of formula (III) by reacting the compounds of formula (III) inways described in the literature to convert a cyano group to an R¹ groupor replace a cyano group with an R¹ group.

Compounds of formula (III) can be prepared by treating3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) with a suitable base,such as lithium diisopropylamide (LDA), and reacting the product soformed with a halide ArHal, wherein Hal is a halogen atom.

3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared bytreating tropinone (V) with tosylmethyl isocyanide in the presence of asuitable base, such as potassium ethoxide. Alternatively,3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared bytreating tropine (X) with thionyl chloride to give3-chloro-8-methyl-8-azabicyclo[3.2.1]octane (XII) and reacting (XII)with cyanide as described in J. Am. Chem. Soc., (1958) 80, 4677.

The compounds of formula (IX) (that is compounds of formula (I) whereinR¹ is hydroxy) can be prepared by reacting compounds of formula (VIII)with a product obtainable by treating a compound of formula ArHal(wherein Hal is a halogen) with a suitable lithium species (such asn-butyl lithium).

The hydroxy group present in the compounds of formula (IX) can befurther reacted by methods known in the art to prepare other compoundsof formula (I).

In further aspects the present invention provides processes forpreparing compounds of formula (I), as hereinbefore described.

In a further aspect the invention provides a method of combating insectand like pests at a locus by applying to the locus or the pests aninsecticidally effective amount of an insecticidal compositioncomprising a compound of formula (I) or an acid addition salt,quaternary ammonium salt or N-oxide derived therefrom.

The compounds of formula (I) can be used to combat and controlinfestations of insect pests such as Lepidoptera, Diptera, Homoptera andColeoptera (including Diabrotica i.e. corn rootworms) and also otherinvertebrate pests, for example, acarine pests. The insect and acarinepests which may be combated and controlled by the use of the inventioncompounds include those pests associated with agriculture (which termincludes the growing of crops for food and fibre products), horticultureand animal husbandry, forestry, the storage of products of vegetableorigin, such as fruit, grain and timber, and also those pests associatedwith the transmission of diseases of man and animals. Examples of insectand acarine pest species which may be controlled by the compounds offormula (I) include: Myzus persicae (aphid), Aphis gossypii (aphid),Aphis fabae (aphid), Aedes aegypti (mosquito), Anopheles spp.(mosquitos), Culex spp. (mosquitos), Dysdercus fasciatus (capsid), Muscadomestica (housefly), Pieris brassicae (white butterfly), Plutellaxylostella (diamond back moth), Phaedon cochleariae (mustard beetle),Aonidiella spp. (scale insects), Trialeurodes spp. (white flies),Bemisia tabaci (white fly), Blattella germanica (cockroach), Periplanetaamericana (cockroach), Blatta orientalis (cockroach) Spodopteralittoralis (cotton leafworm), Heliothis virescens (tobacco budworm)Chortiocetes terminifera (locust), Diabrotica spp. (rootworms), Agrotisspp. (cutworms), Chilo partellus (maize stem borer), Nilaparvata lugens(planthopper), Nephotettix cincticeps (leafhopper), Panonychus ulmi(European red mite), Panonychus citri (citrus red mite), Tetranychusurticae (two-spotted spider mite), Tetranychus cinnabarinus (carminespider mite), Phyllcoptruta oleivora (citrus rust mite),Polyphagotarsonemus latus (broad mite) and Brevipalpus spp. (mites).Further examples include insects which adversely affect the health ofthe public at large and animals.

In order to apply the compounds of formula (I) to the locus of thenematode, insect or acarid pest, or to a plant susceptible to attack bythe nematode, insect or acarid pest, the compound is usually formulatedinto a composition which includes in addition to a compound of formula(I) a suitable inert diluent or carrier material, and, optionally, asurface active agent. The amount of composition generally applied forthe control of nematode pests gives a rate of active ingredient from0.01 to 10 kg per hectare, preferably from 0.1 to 6 kg per hectare.

Thus in another aspect the present invention provides a insecticidal,acaricidal or nematicidal composition comprising an insecticidally,acaricidally or nematicidally effective amount of a compound of formula(I) and a suitable carrier or diluent therefor.

The compositions can be applied to the soil, plant or seed, to the locusof the pests, or to the habitat of the pests, in the form of dustingpowders, wettable powders, granules (slow or fast release), emulsion orsuspension concentrates, liquid solutions, emulsions, seed dressings,fogging/smoke formulations or controlled release compositions, such asmicroencapsulated granules or suspensions.

Dusting powders are formulated by mixing the active ingredient with oneor more finely divided solid carriers and/or diluents, for examplenatural clays, kaolin, pyrophyllite, bentonite, alumina,montmorillonite, kieselguhr, chalk, diatomaceous earths, calciumphosphates, calcium and magnesium carbonates, sulphur, lime, flours,talc and other organic and inorganic solid carriers.

Granules are formed either by absorbing the active ingredient in aporous granular material for example pumice, attapulgite clays, Fuller'searth, kieselguhr, diatomaceous earths, ground corn cobs, and the like,or on to hard core materials such as sands, silicates, mineralcarbonates, sulphates, phosphates, or the like. Agents which arecommonly used to aid in impregnation, binding or coating the solidcarriers include aliphatic and aromatic petroleum solvents, alcohols,polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters,dextrins, sugars and vegetable oils. with the active ingredient. Otheradditives may also be included, such as emulsifying agents, wettingagents or dispersing agents.

Microencapsulated formulations (microcapsule suspensions CS) or othercontrolled release formulations may also be used, particularly for slowrelease over a period of time, and for seed treatment.

Alternatively the compositions may be in the form of liquid preparationsto be used as dips, irrigation additives or sprays, which are generallyaqueous dispersions or emulsions of the active ingredient in thepresence of one or more known wetting agents, dispersing agents oremulsifying agents (surface active agents). The compositions which areto be used in the form of aqueous dispersions or emulsions are generallysupplied in the form of an emulsifiable concentrate (EC) or a suspensionconcentrate (SC) containing a high proportion of the active ingredientor ingredients. An EC is a homogeneous liquid composition, usuallycontaining the active ingredient dissolved in a substantiallynon-volatile organic solvent An SC is a fine particle size dispersion ofsolid active ingredient in water. In use, the concentrates are dilutedin water and applied by means of a spray to the area to be treated.

Suitable liquid solvents for ECs include methyl ketones, methyl isobutylketone, cyclohexanone, xylenes, toluene, chlorobenzene, paraffins,kerosene, white oil, alcohols, (for example, butanol),methylnaphthalene, trimethylbenzene, trichloroethylene,N-methyl-2-pyrrolidone and tetrahydrofurfuryl alcohol (THFA).

Wetting agents, dispersing agents and emulsifying agents may be of thecationic, anionic or non-ionic type. Suitable agents of the cationictype include, for example, quaternary ammonium compounds, for examplecetyltrimethyl ammonium bromide. Suitable agents of the anionic typeinclude, for example, soaps, salts of aliphatic monoesters of sulphuricacid, for example sodium lauryl sulphate, salts of sulphonated aromaticcompounds, for example sodium dodecylbenzenesulphonate, sodium, calciumor ammonium lignosulphonate, or butylnaphthalene sulphonate, and amixture of the sodium salts of diisopropyl- and triisopropylnaphthalenesulphonates. Suitable agents of the non-ionic type include, for example,the condensation products of ethylene oxide with fatty alcohols such asoleyl alcohol or cetyl alcohol, or with alkyl phenols such as octylphenol, nonyl phenol and octyl cresol. Other non-ionic agents are thepartial esters derived from long chain fatty acids and hexitolanhydrides, the condensation products of the said partial esters withethylene oxide, and the lecithins.

These concentrates are often required to withstand storage for prolongedperiods and after such storage, to be capable of dilution with water toform aqueous preparations which remain homogeneous for a sufficient timeto enable them to be applied by conventional spray equipment. Theconcentrates may contain 10-85% by weight of the active ingredient oringredients. When diluted to form aqueous preparations such preparationsmay contain varying amounts of the active ingredient depending upon thepurpose for which they are to be used.

The compounds of formula (I) may also be formulated as powders (dry seedtreatment DS or water dispersible powder WS) or liquids (flowableconcentrate FS, liquid seed treatment LS, or microcapsule suspension CS)for use in seed treatments.

In use the compositions are applied to the insect pests, to the locus ofthe pests, to the habitat of the pests, or to growing plants liable toinfestation by the pests, by any of the known means of applyingpesticidal compositions, for example, by dusting, spraying, orincorporation of granules.

The compound of formula (I) may be the sole active ingredient of thecomposition or it may be admixed with one or more additional activeingredients such as insecticides, synergists, herbicides, fungicides orplant growth regulators where appropriate. Suitable additional activeingredients for inclusion in admixture with a compound of formula (I)may be compounds which will broaden the spectrum of activity of thecompositions of the invention or increase their persistence in thelocation of the pest. They may synergise the activity of the compound offormula (I) or complement the activity for example by increasing thespeed of effect or overcoming repellency. Additionally multi-componentmixtures of this type may help to overcome or prevent the development ofresistance to individual components. The particular additional activeingredient included will depend upon the intended utility of the mixtureand the type of complementary action required. Examples of suitableinsecticides include the following:

a) Pyrethroids such as permethrin, esfenvalerate, deltamethrin,cyhalothrin in particular lambda-cyhalothrin, biphenthrin,fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids or exampleethofenprox, natural pyrethrin, tetramethrin, s-bioallethrin,fenfluthrin, prallethrin and5-benzyl-3-furylmethyl-(E-(1R,3S)-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropane carboxylate;

b) Organophosphates such as profenofos, sulprofos, methyl parathion,azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos,monocrotophos, profenophos, triazophos, methamidophos, dimethoate,phosphamidon, malathion, chloropyrifos, phosalone, terbufos,fensulfothion, fonofos, phorate, phoxim, pyrimiphos-methyl,pyrimiphos-ethyl, fenitrothion or diazinon;

c) Carbamates (including aryl carbamates) such as pirimicarb,cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb,thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur or oxamyl;

d) Benzoyl ureas such as triflumuron, or chlorfluazuron;

e) Organic tin compounds such as cyhexatin, fenbutatin oxide,azocyclotin;

f) Macrolides such as avermectins or milbemycins, for example such asabamectin, ivermectin, and milbemycin;

g) Hormones and pheromones;

h) Organochlorine compounds such as benzene hexachloride, DDT, chlordaneor dieldrin;

i) Amidines, such as chlordimeform or amitraz;

j) Fumigant agents;

k) Imidacloprid;

l) spinosad.

In addition to the major chemical classes of insecticide listed above,other insecticides having particular targets may be employed in themixture if appropriate for the intended utility of the mixture. Forinstance selective insecticides for particular crops, for examplestemborer specific insecticides for use in rice such as cartap orbuprofezin can be employed. Alternatively insecticides specific forparticular insect species/stages for example ovo-larvicides such aschlofentezine, flubenzimine, hexythiazox and tetradifon, motilicidessuch as dicofol or propargite, acaricides such as bromopropylate,chlorobenzilate, or growth regulators such as hydramethylron,cyromazine, methoprene, chlorofluazuron and diflubenzuron may also beincluded in the compositions.

Examples of suitable synergists for use in the compositions includepiperonyl butoxide, sesamax, safroxan and dodecyl imidazole.

Suitable herbicides, fungicides and plant-growth regulators forinclusion in the compositions will depend upon the intended target andthe effect required.

An example of a rice selective herbicide which can be included ispropanil, an example of a plant growth regulator for use in cotton is"Pix", and examples of fungicides for use in rice include blasticidessuch as blasticidin-S. The ratio of the compound of formula (I) to theother active ingredient in the composition will depend upon a number offactors including type of target, effect required from the mixture etc.However in general, the additional active ingredient of the compositionwill be applied at about the rate at which it is usually employed, or ata slightly lower rate if synergism occurs.

The invention is illustrated by the following Examples. Examples 1-25illustrate the preparation of a range of compounds of formula (I).Examples 26-33 illustrate compositions suitable for the application ofthe compounds of formula (I) according to the invention. The followingingredients are referred to by their Registered Trade Marks and have thecomposition as shown below.

    ______________________________________                                        Registered Trade Mark                                                                          Composition                                                  ______________________________________                                        Synperonic NP8 } Nonylphenol-ethylene oxide                                     Synperonic NP13 } condensate                                                  Synperonic OP10 }                                                             Aromasol H Alkylbenzene solvent                                               Solvesso 200 Inert organic diluent                                            Keltrol Polysaccharide                                                      ______________________________________                                    

Throughout the Examples references to Compound Nos. refer to compoundsnumbered on Table I above. Selected NMR data and melting point data arepresented in the Examples. For NMR data, no attempt has been made tolist every absorption. The following abbreviations are used throughoutthe Examples:

    ______________________________________                                        mp    = melting point (uncorrected)                                                                   ppm    = parts per million                              s = singlet t = triplet                                                       m = multiplet dd = double doublet                                             d = doublet q = quartet                                                     ______________________________________                                    

EXAMPLE 1

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-formyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 1).

Stage 1

A few drops of dilute hydrochloric acid were added to a solution of2,5-dimethoxytetrahydrofuran (16.5 g) in water (70 ml). After stirringat room temperature for 30 minutes 2,2,2-trifluoroethylaminehydrochloride (16.9 g), acetonedicarboxylic acid (18.3 g) and sodiumacetate (10.0 g) were added and the mixture stirred at room temperaturefor 2 days. The mixture was diluted to 500 ml with water, saturated withpotassium carbonate and extracted with ethyl acetate (twice). Thecombined organic extracts were washed with aqueous potassium carbonate,dried (magnesium sulfate) and evaporated under reduced pressure.Distillation (90° C.; 0.1 mmHg) gave8-(2,2,2-trifluoroethyl)-8-azabicyclo-[3.2.1]octan-3-one (8.7 g).

Stage 2

Potassium tert-butoxide (5.4 g) was added slowly with cooling to astirred solution of8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (4.0 g) andtosylmethyl isocyanide (4.9 g) in 1,2-dimethoxyethane (80 ml, dry) andethanol (5 ml, dry) under nitrogen at such a rate so as to keep thetemperature below 10° C. The mixture was stirred for 18 hours whileallowing it to warm to room temperature, evaporated under reducedpressure and added to aqueous potassium carbonate solution. The mixturewas extracted with ethyl acetate (twice) and the combined extracts weredried (magnesium sulfate) and evaporated under reduced pressure to givean oil. The mixture was extracted with hexane heated to 65° C. and theextracts allowed to cool and evaporated under reduced pressure to giveexo-3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (2.5 g)mp 90-92° C.

Stage 3

exo-3-Cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (1.09 g)in tetrahydrofuran (10 ml) was added to a stirred solution of lithiumdiisopropylamide [made by adding n-butyl lithium (2.4 ml of a solutionin hexane, 2.5 M) to diisopropylamine (0.61 g) in tetrahydrofuran (10ml)] at -25° C. under nitrogen. After 2 hours at -25° C. the mixture wascooled to -76° C. and 3,5-dichloropyridine (0.74 g) in tetrahydrofuran(1 ml) added. The mixture was allowed to warm to room temperature,stirred for 18 hours and evaporated under reduced pressure. The mixturewas dissolved in ether, washed with water (×2), dried (magnesiumsulfate) and evaporated under reduced pressure. Chromatography [SiO₂ ;diethyl ether:hexane (20:80) to (50:50)] gaveexo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(0.45 g) mp 109.5-111.5° C.

Stage 4

The product from Stage 3 (4.5 g) was dissolved in diethyl ether (dry;100ml), cooled to -10° C. under an atmosphere of nitrogen and a solution oflithium aluminium hydride (30 ml of a solution in diethyl ether, 1 M)added slowly over 20 minutes to the vigorously stirred mixture,maintaining the reaction temperature at -10° C. On complete addition thereaction was stirred at -10° C. for 30 minutes, cooled to -76° C. andtreated with water (30 ml) over 5 minutes allowing the temperature togradually rise to -20° C. The ether soluble fraction was decanted fromthe white precipitate, which was washed with further ether (100 ml). Theether fractions were combined, washed with dilute aqueous sodiumcarbonate solution (10 ml), dried (magnesium sulfate), and evaporatedunder reduced pressure to give an oil. The oil was fractionated bychromatography (silica; hexane:ethyl acetate, 4:1) to give the requiredproduct as a colourless solid, 2.2 g, mp 100.5-101.5° C.

¹ H NMR (CDCl₃): δ 1.50(2H,m); 1.90(2H,m); 2.25(2H,dd); 2.75(2H,dd);2.85(2H,q); 3.50(2H,broad m); 7.50(1H,t); 8.35(1H,d); 8.45(1H,d);9.40(1H,s)ppm.

EXAMPLE 2

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-(2,2-dichloroethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 2).

The product from Example 1, Stage 4 (2.0 g) in carbon tetrachloride(dry, 50 ml) containing triphenyl phosphine (8.3 g) was stirred andheated to reflux under an atmosphere of nitrogen for 9 hours and storedat ambient temperature for 18 hours. The solvent was evaporated underreduced pressure and the brown residue partitioned between aqueoussodium carbonate and ethyl acetate. The organic fraction was separated,dried (magnesium sulfate) and evaporated under reduced pressure. Theresidue was fractionated by chromatography (silica; 4:1 hexane:ethylacetate) to give the required product as a light brown oil, 1.55 g.

¹ H NMR (CDCl₃): δ 1.95(4H,m); 2.25(2H,dd); 2.45(2H,dd); 2.85(2H,q);3.40(2H, broad m); 6.50(1H,s); 7.55(1H,t); 8.40(1H,d); 8.45(1H,d)ppm.

EXAMPLE 3

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-ethynyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 3).

The product from Example 2 (0.2 g) was dissolved in tetrahydrofuran(dry, 3 ml) and cooled to -60° C. with stirring under an atmosphere ofnitrogen. A solution of n-butyl lithium (0.47 ml of a solution inhexane, 2.5 M) was added over 1 hour, the reaction stirred for 1 hour at-60° C. and n-butanol (1 ml) added. The reaction was allowed to warm toambient temperature and dilute aqueous sodium carbonate (5.0 ml) added.The mixture was extracted with ethyl acetate (2×5 ml), dried (magnesiumsulfate) and evaporated under reduced pressure to give a yellow oil. Theoil was fractionated by chromatography (silica; hexane:ethyl acetate4:1) to give the required product as a pale brown oil, 0.075 g.

¹ H NMR (CDCl₃): δ 1.90(2H,broad m); 2.20(2H,dd); 2.30(2H,dd);2.40(1H,s); 2.50(2H,m); 2.85(2H,q); 3.40(2H,broad m); 7.85(1H,t);8.45(1H,broad s); 8.70(1H,broad s)ppm.

EXAMPLE 4

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-hydroxymethyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 4).

exo-3-(5-Chloropyrid-3-yl)-endo-3-formyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(prepared as in Example 1, 0.10 g) was dissolved in anhydrous diethylether (1 ml) and stirred at 0° C. under nitrogen. Lithium aluminiumhydride (0.2 ml of a solution in diethyl ether, 1.0 M) was addeddropwise over 15 minutes, the reaction stirred for a further 30 minutesat 0° C. and allowed to warm to ambient temperature. After 30 minutesthe reaction was treated with water (5 ml) and then ethyl acetate (10ml) added. The organic fraction was separated, dried (magnesium sulfate)and evaporated to give an oil which was fractionated by preparativethick layer chromatography (silica, eluent: ethyl acetate) to give erequired product, 0.054 g, as a colourless oil.

¹ HNMR(CDCl₃): δ 1.80(2H,m); 2.00(2H,m); 2.15(4H,m); 2.85(2H,q);3.40(2H,m); 3.65(2H,m); 7.50(1H,dd); 8.45(1H,d); 8.50(1H,d)ppm.

EXAMPLE 5

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-(2-chloroethynyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 5).

The product from Example 2 (0.12 g) in methanol (1 ml) containing sodiummethoxide (0.016 g) was stirred under nitrogen, heated to 60° C. for 10minutes and allowed to cool to ambient temperature for 18 hours. Furthersodium methoxide (0.1 g) was added and the mixture heated for 2 hours at60° C. and cooled to ambient temperature. The mixture was poured intowater (5 ml), extracted with ethyl acetate (5 ml) and the organicfraction dried (magnesium sulfate) and evaporated under reduced pressureto give an oil which was fractionated by preparative thick layerchromatography (silica; hexane:ethyl acetate 4:1 by volume) to give therequired product as a colourless solid, 0.017 g, mp 74-6° C.

EXAMPLE 6

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 6).

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2-trifuoroethyl)-8-azabicyclo[3.2.1]octane(0.2 g) was dissolved in dry tetrahydrofuran (2 ml) and cooled to -10°C. with stirring under nitrogen. Lithium aluminium hydride (1 ml of asolution in tetrahydrofuran, 1 M) was slowly added over 20 minutes andthe reaction allowed to warm to ambient temperature and stored for 18hours. The reaction was cooled to 0° C., treated with water (5 ml) andextracted with ethyl acetate (2×10 ml). The organic fractions werecombined, dried (magnesium sulfate) and evaporated under reducedpressure to give a brown oil, 0.18 g, which was purified bychromatography (silica; hexane:ethyl acetate 3:1 by volume) to give therequired product as a colourless solid, 0.025 g, mp 104-5° C.

EXAMPLE 7

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-carboxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 7).

Stage 1

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo-[3.2.1]octane(1.7 g) was dissolved in concentrated sulfuric acid (5 ml) and storedfor 40 hours. The mixture was poured into ice/water (100 ml), basifiedwith sodium hydroxide and extracted into ethyl acetate (200 ml), dried(magnesium sulfate) and evaporated under reduced pressure. The residuewas recrystallised from a small volume of ethyl acetate to giveexo-3-(5-chloropyrid-3-yl)-endo-3-carboxamido-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octaneas a colourless solid, 1.4 g, mp 233-4° C.

Stage 2

The product from Stage 1 (1.2 g) was finely powdered, stirred inacetonitrile (20 ml) at ambient temperature and treated portionwise withnitrosonium tetrafluoroborate (1.4 g). The suspension graduallydissolved to give a green solution which subsequently became yellowwhilst gas was evolved from the reaction mixture. The reaction wasstirred for 1 hour, heated to 50° C. for 5 minutes and cooled to ambienttemperature. Water (2 ml) was added, the solvent evaporated underreduced pressure and the residue extracted with sodium hydroxidesolution. The basic, aqueous fraction was washed with ethyl acetate(2×20 ml) and the aqueous fraction separated, taken to pH 7 withhydrochloric acid and extracted with ethyl acetate (2×20 ml). Thecombined organic fractions were dried (magnesium sulfate) and evaporatedunder reduced pressure to give the required product as a light brownsolid, 0.3 g, mp 160-3° C.

EXAMPLE 8

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-carbomethoxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 8).

The product from Example 7 (0.050 g) in acetone (2 ml) containinganhydrous potassium carbonate (0.1 g) and methyl iodide (0.027 g) werestirred at 60° C. in a sealed glass vessel for 2 hours. The solvent wasevaporated and the residue was fractionated by preparative thick layerchromatography (silica; eluent ethyl acetate) to give the requiredproduct was obtained as a colourless solid, 0.023 g, mp 104-5° C.

EXAMPLE 9

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-(N-hydroxyiminomethyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 9).

The aldehyde from Example 1 (0.075 g) in propan-2-ol (1 ml) was treatedwith a solution of hydroxylamine hydrochloride (0.20 g) in water (2 ml)and taken to pH 7 with 50% aqueous sodium hydroxide. The reaction wasstirred at ambient temperature for 1 h, evaporated under reducedpressure and the residue treated with aqueous sodium carbonate andextracted into ethyl acetate (2×5 ml). The combined organic extractswere dried (magnesium sulfate) and evaporated under reduced pressure.The residue was fractionated by thick layer chromatography (silica;ethyl acetate) to give the required product as a colourless solid, 0.052g, mp 133-5° C.

exo-3-(5-Chloropyrid-3-yl)-endo-3-(N-methoxyiminomethyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 10), (colourless solid, mp 94-5° C.), was prepared in asimilar procedure using O-methyl hydroxylamine.

EXAMPLE 10

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-(2,2-dicyanoethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 11).

The aldehyde from Example 1 (0.33 g), malononitrile (5 ml) and ammoniumacetate (0.1 g) were heated in a sealed glass vessel to 100° C. withstirring for 1 hour under an atmosphere of nitrogen. The reaction waspoured into aqueous sodium carbonate solution and extracted with ethylacetate (3×20 ml). The combined organic phase was washed with aqueoussodium carbonate solution (20 ml), dried (magnesium sulfate) andevaporated under reduced pressure to give a brown oil. The oil wasfractionated by preparative thick layer chromatography (silica; 40%ethyl acetate:hexane) and the oil obtained heated to 125° C. at 1 mm Hgto remove traces of malononitrile to give the required product as abrown gum, 0.080 g.

¹ H NMR (CDCl₃): δ 1.75(2H,m); 2.10(2H,m); 2.50(2H,dd); 2.75(2H,dd);2.85(2H,q); 3.50(2H,broad signal); 7.60(1H,t); 7.65(1H,s); 8.40(1H,broadsignal); 8.55(1H,broad signal)ppm.

EXAMPLE 11

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-difluoromethyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 12).

The aldehyde from Example 1 (0.10 g) in diethylaminosulfurtrifluoride (1ml) was stirred at 35° C. for 9 hours and stored at ambient temperaturefor 18 hours. The mixture was poured into ice/water (100 ml), basifiedwith potassium carbonate, extracted with ethyl acetate (100 ml), dried(magnesium sulfate) and evaporated under reduced pressure to give anoil, 0.075 g. The oil was fractionated by chromatography (silica,hexane:tert-butyl methyl ether 4:1 by volume) to give the requiredproduct (0.006 g).

¹ H NMR (CDCl₃): δ 1.70(2H,m); 2.10(2H,m); 2.35(4H,m); 2.85(2H,q);3.45(2H,m); 6.00(1H,t,J=60 Hz); 7.60(1H,dd); 8.40(1H,d); 8.50(1H,d)ppm.

EXAMPLE 12

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-trifluoromethyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 13).

The acid from Example 7 (0.6 g) was dissolved in anhydrous hydrofluoricacid (9.6 g) in a Monel 400 autoclave. Sulfur tetrafluoride (6 g) waspressurised into the mixture which was gradually heated from ambienttemperature to 100° C. for 12 hours. The autoclave was cooled in stagesto -15° C. and the gases vented to waste. The residual brown solutionwas poured onto ice (50 g), the organic material extracted withdichloromethane (3×20 ml), the combined organic phase washed with water(twice), dried (magnesium sulfate) and evaporated under reducedpressure. The residue was treated with aqueous hydrochloric acid (40 ml,2 M) and washed with ethyl acetate (2×20 ml). The aqueous phase wasbasified with sodium carbonate, extracted with ethyl acetate (2×20 ml),dried (magnesium sulfate) and evaporated under reduced pressure to givethe required product as a brown gum, 0.25 g.

¹ H NMR (CDCl₃): δ 1.70(2H,m); 1.90(4H,m); 2.60(2H,q); 3.00(2H,dd);3.45(2H,m); 7.75(1H,dd); 8.40(1H,d); 8.60(1H,d)ppm.

EXAMPLE 13

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-ethenyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 14).

Methyl triphenyl phosphonium bromide (0.71 g) was suspended in drytetrahydofuran (10 ml) and stirred under nitrogen at ambient temperaturewhilst a solution of lithium bis(trimethylsilyl) amide (2.0 ml of asolution in tetrahydrofuran, 1 h was slowly added. The yellow mixturewas stirred for 20 minutes and the aldehyde from Example (0.33 g) added.The reaction was heated to 40° C. for 10 minutes, treated with water (25ml) and extracted with ethyl acetate (25 ml). The organic phase wasseparated, extracted with hydrochloric acid (2×25 ml, 2 M) and theorganic fraction discarded. The aqueous phase was made basic with sodiumcarbonate, extracted with diethyl ether (2×25 ml), dried (magnesiumsulfate) and evaporated under reduced pressure to give the requiredproduct as an off-white solid, 0.29 g, mp 78-80° C.

The following analogues were made using a similar procedure:

exo-3-(5-Chloropyrid-3-yl)-endo-3-(E)-(2-cyclopropylethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound no. 15), yellow oil; ¹ H NMR (CDCl₃): δ 0.05(2H,m);0.35(2H,m); 0.75(1H,m); 1.65(2H,m); 1.85(2H,m); 2.05(4H,m);2.60(2H,q);3.15(2H,m); 5.40(1H,t); 6.70(1H,d); 7.45(1H,broad signal); 8.15(1H,broadsignal); 8.30(1H,broad signal)ppm.

(E) and (Z) (ratio1:2)-exo-3-(5-Chloropyrid-3-yl)-endo-3-(2-methoxyethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 16), oil; ¹ H NMR (CDCl₃): δ 1.80-2.30(6H,m); 2.50(2H,dd);2.85(2H,q); 3.35(2H,m); 3.50(3H,s); 4.60(Z isomer,d); 5.00(E isomer,d);5.80(Z isomer,d); 6.30(E isomer,d); [7.50(dd); 7.60(dd); 8.35(d);8.40(d); 8.50(d) E/Z isomers]ppm.

exo-3-(5-Chloropyrid-3-yl)-endo-3-(E)(2-chloroethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 17), oil; ¹ H NMR (CDCl₃): δ 1.90(4H,m); 2.10(2H,dd);2.35(2H,dd); 2.80(2H,q); 3.40(2H,broad signal); 6.10(2H,m); 7.45(1H,t);8.40(2H,m)ppm.

exo-3-(5-Chloropyrid-3-yl)-endo-3-(Z)(2-chloroethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 18), colourless solid, mp 96.0-98.5° C. Compounds 17 and18 were separated by chromatography (silica; hexane/ethyl acetate 3:1 byvolume) from a 2:1 mixture.

exo-3-(5-Chloropyrid-3-yl)-endo-3-(E)-(2-phenethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 19), yellow oil; ¹ H NMR (CDCl₃): δ 1.90(4H,m);2.40(4H,m); 2.90(2H,q); 3.40(2H,broad signal); 6.35(1H,d); 6.55(1H,d);7.20-7.35(5H,m); 7.55(1H,dd); 8.35(1H,d); 8.45(1H,d)ppm.

exo-3-(5-Chloropyrid-3-yl)-endo-3-(E)-(2-cyanoethenyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 20), colourless solid, mp 129-133° C.

EXAMPLE 14

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-methoxymethyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No 21).

The alcohol from Example 4 (0.2 g) was dissolved with stirring indimethyl sulfoxide (2 ml) containing powdered potassium hydroxide (1 g)and methyl iodide (1 ml) at ambient temperature. The red-brown mixturewas stirred for 1 hour, poured into water (20 ml), extracted withdiethyl ether (2×20 ml), dried (magnesium sulfate) and evaporated underreduced pressure to give a brown oil. The oil was fractionated by thicklayer chromatography (silica; ethyl acetate) to give the requiredproduct, 0.03 g, as a colourless oil.

¹ H NMR (CDCl₃): δ 1.80(2H,m); 2.00-2.25(6H,m); 2.85(2H,q); 3.20(3H,s);3.40(4H,broad signal); 7.50(1H,t); 8.40(2H,dd)ppm.

EXAMPLE 15

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-(2-(pyrid-3-yl)ethynyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 22).

The alkyne from Example 3 (0.38 g), 3-bromopyridine (0.5 g),tetrakis(triphenylphosphine) palladium (0) (0.05 g, catalyst), copperbromide (0.05 g, catalyst), in triethylamine (1 ml) were stirred at 40°C. under an atmosphere of nitrogen for 30 minutes. The mixture wasevaporated under reduced pressure, extracted with ethyl acetate (50 ml)and washed with sodium carbonate solution. The organic phase wasextracted with hydrochloric acid (2×25 ml, 2 M) and the aqueous phaseseparated. The aqueous phase was washed with ethyl acetate (2×25 ml),basified with sodium carbonate solution and the aqueous phasere-extracted with ethyl acetate (2×50 ml). The combined organic phaseextracts were dried (magnesium sulfate) and evaporated under reducedpressure to give a yellow oil which was fractionated by preparativethick layer chromatography (silica; ethyl acetate) to give the requiredproduct as an off-white solid, 0.10 g, mp 115.0-119.5° C.

¹ H NMR (CDCl₃): δ 2.00(2H,m); 2.30(4H,m); 2.50(2H,m); 2.90(2H,m);3.50(2H,m); 7.20(1H,dd); 7.70(1H,double triplet); 7.80(1H,t);8.50(1H,d); 8.55(1H,dd); 8.70(1H,d); 8.80(1H,d)ppm.

The following analogues were prepared using a similar procedure:-

exo-3-(5-Chloropyrid-3-yl)-endo-3-(2-(4-fluorophenyl)ethynyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No 23), brown solid, mp 96-101° C. ¹ H NMR (CDCl₃): δ2.00(2H,m); 2.30(4H,m); 2.60(2H,m); 2.90(2H,q); 3.50(2H,m); 7.00(2H,m);7.40(2H,m); 7.85(1H,dd); 8.45(1H,d); 8.80(1H,d)ppm.

exo-3-(5-Chloropyrid-3-yl)-endo-3-(2-(pyrid-2-yl)ethynyl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 24), brown solid, mp 110-114° C.

EXAMPLE 16

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-pivaloyloxymethyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 25).

The alcohol from Example 4 (0.2 g) was dissolved in dichloromethane(dry; 8 ml) and treated with pivaloyl chloride (0.086 ml) andN,N-diisopropylethylamine (0.12 ml) at ambient temperature. The mixturewas stirred for 22 hours, heated to reflux for 6 hours and allowed tocool to ambient temperature for 18 hours. The reaction was treated withwater (50 ml) and extracted with ethyl acetate (50 ml). The mixture wasacidified with hydrochloric acid (50 ml, 2 M) and the acidic fractioncollected. The organic phase was further treated with hydrochloric acid(50 ml, 2 M) and the aqueous, acidic fractions combined and washed withethyl acetate. The aqueous fraction was separated, basified with sodiumhydrogen carbonate solution and extracted with ethyl acetate (2×50 ml).The organic phase extracts were combined, dried (magnesium sulfate) andevaporated under reduced pressure to give a brown oil which solidifiedon cooling. The solid was washed with a small volume of 20% diethylether in hexane to give the required product as an off-white solid, 0.13g, mp 155-157° C.

EXAMPLE 17

This Example illustrates the preparation ofexo-3-(3,5-difluorophenyl)-endo-3-(N-acetylaminomethyl)-8-(methyl)-8-azabicyclo[3.2.1]octane (Compound No. 26).

Stage 1

Potassium tert-butoxide (22.4 g) was added portionwise to a stirredmixture of tropinone (11.58 g) and tosylmethyl isocyanide (21.2 g) indry 1,2-dimethoxyethane (240 ml) and ethanol (8 ml) at 0° C. under anatmosphere of nitrogen at such a rate to maintain the reactiontemperature between 0° C. and 10° C. The mixture was allowed to warm toroom temperature and stirred for a further 4 hours. After standing themixture at room temperature for 3 days it was filtered and the solidresidue washed with 1,2-dimethoxyethane. The filtrate was evaporatedunder reduced pressure and fractionated by chromatography [silica, 10%methanol in dichloromethane) to giveexo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (9.1 g).

Stage 2

exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (13.6 g )in drytetrahydrofuran (80 ml) was added dropwise to a stirred solution oflithium diisopropylamide [made by adding n-butyl lithium (40 ml of asolution in hexane, 2.5 M) to diisopropylamine (14.0 ml) intetrahydrofuran (80 ml)] at -25° C. under an atmosphere of nitrogen. Themixture was stirred at -25° C. for 0.5 hours and cooled to -78° C.1,3,5-Trifluorobenzene (12.0 g) in tetrahydrofuran (80 ml) was addeddropwise at such a rate to maintain the temperature below -65° C. Themixture was allowed to warm to room temperature overnight and thenpoured into water and extracted with dichloromethane. The combinedextracts were washed with brine, dried (MgSO₄) and evaporated underreduced pressure to give a yellow solid. This was recrystallised fromdiethyl ether to giveexo-3-(3,5-difluorophenyl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane.The mother liquor from the recrystallisation was chromatographed[silica, 10% methanol in dichloromethane] to give further desiredproduct, giving a total yield of 11.2 g.

Stage 3

The product from Stage 2 (2.5 g) in dry diethyl ether (15 ml) wasstirred at 0° C. under an atmosphere of nitrogen, lithium aluminiumhydride (15.3 ml of a diethyl ether solution, 1.0 M) was added dropwiseand the reaction was stirred for a further 30 minutes. The reaction wasallowed to warm to ambient temperature and stored for 18 hours. Themixture was re-cooled to 0° C., quenched with a mixture ofmethanol/water/acetic acid (8:2:1), stirred for 1.5 hours, diluted withaqueous sodium chloride solution and made basic with aqueous sodiumhydroxide (2 M). The mixture was extracted with dichloromethane, dried(magnesium sulfate) and evaporated under reduced pressure and theresidue fractionated by chromatography (silica,dichloromethane:methanol) to giveexo-3-(3,5-difluorophenyl)-endo-3-aminomethyl-8-methyl-8-azabicyclo[3.2.1]octane,1.9 g, mp 113-7° C. (Compound No. 27).

Stage 4

The product from Stage 3 (0.5 g) was dissolved in dry diethyl ether (10ml) containing dry triethylamine (0.26 ml) at 0° C. with stirring andtreated with acetyl chloride (0.15 g). The reaction was stirred at 0° C.for 1 hour, allowed to warm to ambient temperature and the mixtureextracted with dichloromethane. The extract was washed with aqueoussodium chloride solution, water, dried (magnesium sulfate) andevaporated under reduced pressure to give the required product as ayellow solid, 0.35 g, mp 56.5-57.2° C.exo-3-(3,5-Difluorophenyl)-endo-3-(N-benzoylaminomethyl)-8-methyl-8-azabicyclo[3.2.1]octane(Compound No. 28), colourless solid, mp 149.3° C., was prepared in asimilar way using benzoyl chloride.

EXAMPLE 18

This Example illustrates the preparation ofexo-3-(3,5-difluorophenyl)-endo-3-carbomethoxyamino-8-methyl-8-azabicyclo[3.2.1]octane(Compound No. 29).

The carboxamide from Example 7, Stage 1 (0.56 g) was dissolved inmethanol (10 ml) containing sodium methoxide (0.325 g) at ambienttemperature with stirring. Bromine (0.11 ml) was added to the solutionand the mixture stirred for 2 hours. The solvent was evaporated underreduced pressure and the residue extracted with diethyl ether (200 ml).The organic phase was washed with water, dried (magnesium sulfate) andevaporated under reduced pressure to leave a residue. The residue wasfractionated by chromatography (silica, 20% methanol in dichloromethane)to give the required product, 0.16 g, mp 120-2° C.

EXAMPLE 19

This Example illustrates the preparation ofexo-3-(pyrid-3-yl)-endo-3-methoxy-8-methyl-8-azabicyclo[3.2.1]octane(Compound No. 30).

Stage 1

2-Chloro-5-aminopyridine (15.0 g) was dissolved in concentratedhydrochloric acid (150 ml) at 0° C. with stirring. Sodium nitrite (10.47g) in water (5 ml) was added dropwise maintaining the reaction below 5°C. Sodium iodide (26.23 g) in water (20 ml) was slowly added to theorange solution at 0-5° C. and stirred for 1 hour and allowed to warm toambient temperature over 18 hours. The reaction was diluted with water(300 ml), the solid which had formed filtered from solution anddissolved in ethyl acetate. The organic phase was washed with diluteaqueous sodium hydroxide, aqueous sodium hydrogen carbonate, dried(magnesium sulfate) and evaporated under reduced pressure. The residuewas fractionated by chromatography (silica hexane/5-10% ethyl acetate)to give 2-chloro-5-iodopyridine, 14.9 g, as a colourless solid, mp89-90° C.

Stage 2

N-Carboethoxytropinone (1.0 g) was dissolved with stirring in drychloroform (2.5 ml), cooled to 0° C. under an atmosphere of nitrogen andtreated with trimethylsilyl iodide (1.22 g). The mixture was heated toreflux for 5 hours, stored at ambient temperature for 2 days andre-cooled to 0° C. under an atmosphere of nitrogen with stirring. Thereaction was treated dropwise with a solution of hydrogen chloride inmethanol (2.0 ml, 5 M), stirred for 1.5 hours and evaporated underreduced pressure. The brown solid obtained was treated with toluene andthe resulting mixture evaporated under reduced pressure. The residualsolid was suspended in dry dichloromethane (5 ml), cooled to 0° C. underan atmosphere of nitrogen and a solution of pyridine (1.0 g) and4-N,N-dimethylaminopyridine (5 mg, catalyst) in dichloromethane (5 ml)added. The solution was stirred for 0.5 hour, di-tert-butyl dicarbonate(1.43 g) added dropwise and the reaction allowed to warm to ambienttemperature. The mixture was treated with water, extracted withdichloromethane and the combined organic phase washed with aqueouscopper sulfate, water and aqueous sodium chloride, dried (magnesiumsulfate) and evaporated under reduced pressure. The brown oil obtainedwas fractionated by chromatography (silica, 30% ethyl acetate/hexane) togive N-carbo-tert-butoxy-tropinone as a pale yellow solid, 0.91 g, mp65.0-66.5° C.

Stage 3

2-Chloro-5-iodopyridine (0.32 g) was dissolved in a 2:1 mixture ofdiethyl ether and tetrahydrofuran (12 ml), cooled to -78° C. under anatmosphere of nitrogen with stirring and treated dropwise with n-butyllithium (0.53 ml of a solution in hexane, 2.5 M). The deep red solutionwas stirred at -78° C. for 20 minutes, and N-carbo-tert-butoxy-tropinone(0.30 g) in diethyl ether (3 ml) was added dropwise, after which thereaction mixture was allowed to warm to ambient temperature slowly over18 hours. Saturated, aqueous ammonium chloride solution was added andthe mixture extracted (3 times) with ethyl acetate. The combined organicphase was dried (magnesium sulfate) and evaporated under reducedpressure to give a gum which was fractionated by chromatography (silica,hexane:ethyl acetate, 1:1) to giveexo-3-(6-chloropyrid-3-yl)-endo-3-hydroxy-8-(N-carbo-tert-butoxy)-8-azabicyclo[3.2.1]-octane(Compound No. 43) as a yellow, foamy solid, 0.24 g.

¹ HNMR (CDCl₃): δ 1.45(9H,s); 1.75-1.95(2H,m); 1.95-2.10(2H,m);2.10-2.50(5H,m); 4.2-4.4(2H,m); 7.25(1H,d); 7.65(1H,dd); 8.40(1H,d)ppm.

Stage 4

The product from Stage 3 (0.10 g) was added to a suspension of sodiumhydride (0.015 g) in dry tetrahydrofuran (5 ml) at 0° C. under anatmosphere of nitrogen, stirred for 1 hour and methyl iodide (0.046 g)was added. The reaction was stirred for 2 hours, further methyl iodide(0.02 ml) added and the reaction stored at ambient temperature for 2days. The mixture was treated with water, extracted with ethyl acetate(3 times), the combined organic phase was washed with saturated sodiumchloride solution, dried (magnesium sulfate) and evaporated underreduced pressure to give an oil. The residue was fractionated bychromatography (silica; 25% ethyl acetate in hexane) to giveexo-3-(6-chloropyrid-3-yl)-endo-3-methoxy-8-(N-carbo-tert-butoxy)-8-azabicyclo[3.2.1]octane(Compound No. 31), 0.056 g, yellow oil.

¹ H NMR(CDCl₃): δ 1.45(9H,s); 1.90-2.25(8H,m); 4.20(1H,m); 4.35(1H,m);3.0(3H,s); 7.30(1H,d); 7.60(1H,dd); 8.35(1H,d)ppm.

Stage 5

The product from Stage 4 (0.174 g) was dissolved in methanol (3.5 ml)containing potassium hydroxide (0.028 g) and 5% palladium on charcoal(0.174 g, catalyst) added. The mixture was stirred under an atmosphereof hydrogen for 18 hours, after which time the required hydrogenolysiswas complete. The mixture was filtered, the filtrate evaporated underreduced pressure and the residue extracted into ethyl acetate. Theorganic phase was washed with saturated sodium chloride solution, dried(magnesium sulfate) and evaporated under reduced pressure to giveexo-3-(pyrid-3-yl)-endo-3-methoxy-8-(N-carbo-tert-butoxy)-8-azabicyclo[3.2.1]octane(Compound No. 33), oil, 0.125 g.

¹ H NMR (CDCl₃): δ 1.40(9H,s); 1.90-2.35(8H,m); 3.0(3H,s); 4.25(1H,m);4.35(1H,m); 7.25(1H,dd); 7.65(1H,double triplet), 8.60(1H,broadsignal)ppm.

Stage 6

The product from Stage 5 (0.11 g) was dissolved in formic acid (3.5 ml),heated to reflux for 1 hour and cooled to ambient temperature. Themixture was treated with paraformaldehyde (0.12 g) and heated to refluxwith stirring for 2 hours and stored at ambient temperature for 2 days.The reaction was evaporated under reduced pressure and the residuepartioned between dichloromethane and aqueous sodium hydroxide solution.The phases were separated, the aqueous phase was re-extracted withdichloromethane and the combined organic phase was dried (magnesiumsulfate) and evaporated under reduced pressure to giveexo-3-(pyrid-3-yl)-endo-3-methoxy-8-methyl-8-azabicyclo[3.2.1]octane asa yellow oil, 0.073 g.

¹ H NMR (CDCl₃): δ 2.0-2.35(8H,m); 2.40(3H,s); 2.95(3H,s); 3.30(2H,m);7.30(1H,dd); 7.70(1H,double triplet); 8.50(1H,dd); 8.65(1H,d)ppm.

In a similar procedure to Example 19, Stage 6exo-3-(6-chloropyrid-3-yl)-endo-3-methoxy-8-(N-carbo-tert-butoxy)-8-azabicyclo[3.2.1]octanewas converted toexo-3-(6-chloropyrid-3-yl)-endo-3-methoxy-8-methyl-8-azabicyclo[3.2.1]octane,(Compound No. 32), yellow oil; ¹ H NMR (CDCl₃): δ 1.95-2.15(8H,m);2.35(3H,s); 2.95(3H,s); 3.25(2H,m); 7.30(1H,d); 7.65(1H,dd);8.40(1H,d)ppm.

EXAMPLE 20

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-(tetrazol-5-yl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 34).

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(prepared in Example 1 stage 3, 0.50 g) was dissolved in dryN,N-dimethylformamide (5.0 ml) containing sodium azide (0.13 g) andammonium chloride (0.05 g, catalyst) with stirring and heated to 110° C.in a sealed glass vessel for 43 hours. The mixture was evaporated underreduced pressure and the residue treated with an aqueous solution ofammonium chloride, extracted with ethyl acetate (2×10 ml), dried(magnesium sulfate) and evaporated under reduced pressure to give acolourless gum. The gum was fractionated by preparative thick layerchromatography (silica; diethyl ether) to give the required product as acolourless solid, 0.13 g, mp 221-222° C.(dec).

¹ HNMR (CDCl₃): δ 1.25(4H,m); 1.75(1H,m); 2.10(2H,d); 2.85(2H,q);3.25(2H,d); 3.45(2H,m); 7.80(1H,m); 8.25(1H,m); 8.40(1H,m)ppm. Molecularion 372.

EXAMPLE 21

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-(5-methyl-1,2,4-oxadiazol-3-yl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 35).

Stage 1

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo-[3.2.1]octane(prepared in Example 1 stage 3, 0.10 g) was added to a mixture ofhydroxylamine hydrochloride (0.15 g) and potassium tert-butoxide (0.28g) in tert-butanol (2 ml) with stirring under an atmosphere of nitrogen.The mixture was heated to 90-100° C. for 20 hours, the mixture cooled,evaporated under reduced pressure and the residue treated with aqueousammonium chloride. The product was extracted into ethyl acetate (2×10ml), dried (magnesium sulfate) and evaporated under reduced pressure togive a colourless oil. The oil was fractionated by preparative thicklayer chromatography (silica; diethyl ether) to giveendo-3-(3-amidoximido)-exo-3-(5-chloropyrid-3-yl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane(Compound No. 36) as a colourless foamy solid, (0.050 g), mp 167-169° C.

Stage 2

The product from Stage 1 (0.050 g) was dissolved in toluene (dry, 2 ml)containing acetic anhydride (0.018 g) with stirring. The mixture washeated to 80° C. for 0.5 hour, then at 110° C. for 11 hours. The mixturewas evaporated under reduced pressure and the residue fractionated bypreparative thick layer chromatography (silica; diethyl ether) to givethe title product as a colourless solid, 0.026 g, mp 106-108° C.

¹ H NMR (CDCl₃): δ 1.50(2H,q); 1.75(2H,m); 2.40(2H,dd); 2.55(3H,s);2.85(2H,q); 3.15(2H,dd); 3.40(2H,m); 7.35(1H,t); 8.40(1H, m); 8.50(1H,m)ppm.

EXAMPLE 22

This Example illustrates the preparation ofendo-3-amino-8-(carboethoxy)-exo-3-(5-chloropyrid-3-yl)-8-azabicyclo[3.2.1]octane(Compound No. 37).

Stage 1

8-(Carboethoxy)-exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane(prepared, for example, as in WO 96/37494, 6.6 g) was dissolved inconcentrated sulfuric acid (40 ml) containing water (10 ml) and stirredat 50° C. for 24 hours. Further concentrated sulfuric acid (20 ml) wasadded and the mixture heated for an additional 7 hours at 50° C. Thereaction mixture was poured into water (500 ml), basified with aqueoussodium hydroxide and the product extracted with ethyl acetate (200 ml)and tert-butyl methyl ether (200 ml). The extracts were combined, dried(magnesium sulfate) and evaporated under reduced pressure to giveendo-8-(carboethoxy)-3-carboxamido-exo-3-(5-chloropyrid-3-yl)-8-azabicyclo[3.2.1]octane(Compound No.38) as a colourless solid (2.65 g). A sample wasrecrystallised from ethyl acetate to give a colourless solid, mp220.0-222.5° C.

Stage 2

The product from Stage 1 (0.10 g) was added to a solution of lithiumhydroxide (0.072 g) in water (2 ml) and 1,4-dioxane (2 ml) and themixture stirred at 40° C. Bromine (0.096 g) was added to the mixture inone portion and the reaction stirred for 1 hour at 40° C. The volatileswere evaporated under reduced pressure and the yellow residue extractedinto ethanol (5 ml). The ethanolic solution was evaporated under reducedpressure to give a yellow semi-solid, which was extracted with hot ethylacetate (10 ml). The extracts were evaporated under reduced pressure togive a yellow oil. The oil was fractionated by preparative thick layerchromatography (silica; ethyl acetate) to give the title product as apale yellow oil, 0.036 g.

¹ H NMR (CDCl₃): δ 1.30(3H,t); 1.80(2H,d); 1.95-2.15(2H,m);2.20-2.45(4H,m); 4.20(2H,q); 4.30(2H,m); 7.55(1H,t); 8.40(1H,d);8.50(1H,d)ppm.

EXAMPLE 23

This Example illustrates the preparation of8-(carboethoxy)-exo-3-(5-chloropyrid-3-yl)-endo-3-N-formylamino-8-azabicyclo[3.2.1]octane(Compound No. 39).

endo-3-Amino-8-(carboethoxy)-exo-3-(5-chloropyrid-3-yl)-8-azabicyclo[3.2.1]octane(1.00 g) and formic acid (10 ml, 98%) were stirred and heated to refluxfor 5 hours. The excess formic acid was evaporated under reducedpressure, the residue was treated with toluene (2×50 ml), each timeevaporating under reduced pressure to remove residual formic acid. Theresidue was fractionated by eluting through a column of silica withethyl acetate followed by preparative thick layer chromatography (basicalumina; ethyl acetate) to give the required product as a colourlesssolid, 0.19 g, mp 186.5-188.5° C.

¹ H NMR (CDCl₃): δ 1.30(3H,t); 2.0-2.80(8H,m); 4.15(2H,q); 4.45 (2H,m);6.75(1H,m); 7.65(1H,t); 8.15(1H,m); 8.50(1H,d); 8.40(1H,d)ppm.

EXAMPLE 24

This Example illustrates the preparation of8-(carboethoxy)-exo-3-(5-chloropyrid-3-yl)-endo-3-isocyano-8-azabicyclo[3.2.1]octane(Compound No. 40).

8-(Carboethoxy)-exo-3-(5-chloropyrid-3-yl)-endo-3-N-formylamino-8-azabicyclo-[3.2.1]octane(0.15 g) was dissolved in dry dichloromethane (10 ml,) containingtriethylamine (0.5 ml) and the stirred mixture was cooled to 0° C.Phosphorus oxychloride (0.5 ml) was added dropwise and the reactionstirred at 0° C. for 3 hours. The mixture was then evaporated underreduced pressure. The residue was treated with an aqueous solution ofsodium bicarbonate and the product extracted into ethyl acetate (2×10ml), the organic extracts were combined, dried (magnesium sulfate) andevaporated under reduced pressure to give a brown gum. The gum wasfractionated by preparative thick layer chromatography (silica; ethylacetate) to give the required product, 0.12 g, colourless gum.

¹ H NMR (CDCl₃): δ 1.30(3H,t); 2.10-2.50(8H,m); 4.20(2H,q); 4.50(2H,m);7.75(1H,t); 8.55(2H,t)ppm.

EXAMPLE 25

This Example illustrates the preparation of8-(carboethoxy)-exo-3-(5-chloropyrid-3-yl)-endo-3-nitro-8-azabicyclo[3.2.1]octane(Compound No. 41).

Stage 1

Acetonitrile (90 ml) containing water (9 ml) was stirred in a glassreaction vessel, cooled to -10° C. and purged with nitrogen. Fluorinediluted with nitrogen was slowly bubbled into the mixture, at a rate of5 ml of fluorine per minute, for 0.5 hour and sodium fluoride (5.0 g)added to the solution. The mixture was stirred for 10 minutes at -5° C.,cooled to -15° C. andendo-3-amino-8-carbethoxy-exo-3-(5-chloropyrid-3-yl)-8-azabicyclo[3.2.1]-octane(0.5 g) in dichloromethane (8 ml) was added and the mixture stirred for10 minutes. The reaction mixture was poured into water (500 ml),basified with sodium hydrogen carbonate and extracted withdichloromethane (3×20 ml). The extracts were combined, washed withwater, dried (magnesium sulfate) and evaporated under reduced pressure.The residue was fractionated by preparative thick layer chromatography(silica; 10% methanol by volume in ethyl acetate) to give8-(carboethoxy)-exo-3-(5-chloropyrid-3-yl-1-oxide)-endo-3-nitro-8-azabicyclo[3.2.1]octane(Compound No. 42) as a colourless solid, 0.11 g, mp 217° C. (dec).

¹ H NMR (CDCl₃): δ 1.25(3H,t); 1.70(2H,m); 2.00(2H,m); 2.40(2H,m);3.45(2H,d); 4.15(2H,m); 4.45(2H,m); 7.30(1H,t); 8.20(1H,d);8.25(1H,d)ppm.

Stage 2

The product from Stage 1 (0.050 g) was dissolved in chloroform (2 ml)with stirring and phosphorus trichloride (0.2 ml) was added. The mixturewas heated to 60° C. in a sealed glass vessel for 2 hours, cooled toambient temperature and extracted with chloroform (5 ml). The extractwas treated with a solution of aqueous sodium carbonate, the organicphase separated, dried (magnesium sulfate) and evaporated under reducedpressure to give the title product, 0.039 g, oil.

¹ H NMR (CDCl₃): δ 1.25(3H,t); 1.70(2H,m); 2.00(2H,m); 2.45(2H,m);3.55(2H,m); 4.15(2H,q); 4.45(2H,m); 7.70(1H,t); 8.45(1H,m);8.50(1H,m)ppm. Molecular ion 339.

EXAMPLE 26

This Example illustrates an emulsifiable concentrate composition whichis readily convertible by dilution with water into a liquid preparationsuitable for spraying purposes. The concentrate has the followingcomposition:

    ______________________________________                                                           % Weight                                                   ______________________________________                                        Compound No. 1       25.5                                                       SYNPERONIC NP13 2.5                                                           Calcium dodecylbenzenenesulphonate 2.5                                        AROMASOL H 70                                                               ______________________________________                                    

EXAMPLE 27

This Example illustrates a wettable powder composition which is readilyconvertible by dilution with water into a liquid preparation suitablefor spraying purposes. The wettable powder has the followingcomposition:

    ______________________________________                                                        % Weight                                                      ______________________________________                                        Compound No. 13   25.0                                                          Silica 25.0                                                                   Sodium lignosulphonate 5.0                                                    Sodium lauryl sulphate 2.0                                                    Kaolinite 43.0                                                              ______________________________________                                    

EXAMPLE 28

This Example illustrates a dusting powder which may be applied directlyto plants or other surfaces and comprises 1% by weight of Compound No.25 and 99% by weight of talc.

EXAMPLE 29

This Example illustrates a concentrated liquid formulation suitable forapplication by ultra low volume techniques after mixing with paraffinicdiluents.

    ______________________________________                                                       % Weight                                                       ______________________________________                                        Compound No. 29  90.0                                                           SOLVESSO 200 10.0                                                           ______________________________________                                    

EXAMPLE 30

This Example illustrates a capsule suspension concentrate which isreadily convertible by dilution with water to form a preparationsuitable for application as an aqueous spray.

    ______________________________________                                                             % Weight                                                 ______________________________________                                        Compound No. 43        10.0                                                     Alkylbenzene solvent (e.g. AROMASOL H) 5.0                                    Toluene di-isocyanate 3.0                                                     Ethylenediamine 2.0                                                           Polyvinyl alcohol 2.0                                                         Bentonite 1.5                                                                 Polysaccharide (e.g. KELTROL) 0.1                                             Water 76.4                                                                  ______________________________________                                    

EXAMPLE 31

A ready for use granular formulation:

    ______________________________________                                                             % Weight                                                 ______________________________________                                        Compound No. 4         0.5                                                      SOLVESSO 200 0.2                                                              nonylphenol ethoxylate (eg Synperonic NP8) 0.1                                Calcium carbonate granules (0.3-0.7 mm) 99.2                                ______________________________________                                    

EXAMPLE 32

An aqueous suspension concentrate:

    ______________________________________                                                                  % Weight                                            ______________________________________                                        Compound No. 8              5.0                                                 Kaolinite 15.0                                                                Sodium lignosulphonate 3.0                                                    nonylphenolethoxylate (eg Synperonic NP 8) 1.5                                propylene glycol 10.0                                                         Bentonite 2.0                                                                 Polysaccharide (eg Keltrol) 0.1                                               Bactericide (eg Proxel; Proxel is a registered Trade Mark) 0.1                Water 63.3                                                                  ______________________________________                                    

EXAMPLE 33

This Example illustrates a water dispersible granule formulation.

    ______________________________________                                                          % Weight                                                    ______________________________________                                        Compound No. 20     5                                                           Silica 5                                                                      Sodium lignosulphate 10                                                       Sodium dioctylsulphosuccinate 5                                               Sodium acetate 10                                                             Montmorillonite powder 65                                                   ______________________________________                                    

EXAMPLE 34

This Example illustrates the insecticidal properties of the compounds offormula (I). The activity of the compounds of formula (I) was determinedusing a variety of pests. The pests were treated with a liquidcomposition containing 500 parts per million (ppm) by weight of thecompound unless otherwise stated. The compositions were made bydissolving the compound in acetone and ethanol (50:50) mixture anddiluting the solutions with water containing 0.05% by weight of awetting agent sold under the trade name "SYNPERONIC" NP8 until theliquid composition contained the required concentration of the compound."SYNPERONIC" is a Registered Trade Mark.

The test procedure adopted with regard to each pest was basically thesame and comprised supporting a number of the pests on a medium whichwas usually a substrate, a host plant or a foodstuff on which the pestsfeed, and treating either or both the medium and the pests with thecompositions. The mortality of the pests was then assessed at periodsusually varying from two to five days after the treatment.

The results of the tests against peach aphid (Myzus persicae) arepresented below. The results indicate a grading of mortality (score)designated as A, B or C wherein C indicates less than 40% mortality, Bindicates 40-79% mortality and A indicates 80-100% mortality; "-"indicates that either the compound was not tested or no meaningfulresult was obtained. In this test Chinese cabbage leaves were infestedwith aphids, the infested leaves were sprayed with the test composition,and the mortality assessed after 3 days. Compound Nos. 1, 2, 3, 5, 6, 8,9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 28, 37 and 40gave a mortality score of A.

In addition, in a similar test against red spider mites (Tetranychusurticae) Compounds Nos. 2, 3, 5, 8, 14, 16, 18, 21, 26, 28, 33 and 40gave a mortality score of A. ##STR4##

We claim:
 1. A compound of formula (I): wherein Ar is a substituted orunsubstituted 6-membered heterocyclic ring containing only one nitrogenas the heteroatom and at least one unsaturation (double bond) betweenadjacent atoms in the ring, said heterocyclic ring being optionallyfused to a benzene ring, wherein the substituents, if present, areselected from halogen atoms, cyano, alkyl, alkenyl, alkynyl, alkoxy,haloalkyl, haloalkenyl, alkylthio and alkyl amino groups; R is C₁₋₄alkyl (optionally substituted with cyano, CO₂ (C₁₋₄ alkyl) or phenyl(itself optionally substituted with halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl or C₁₋₄ haloalkoxy)), C₂₋₄ haloalkyl (the α-carbon beingunsubstituted), C₁₋₄ alkoxycarbonyl, C₃₋₄ alkenyl or C₃₋₄ alkynyl;provided that when R is alkenyl or alkynyl said group does not have anunsaturated carbon atom bonding directly to the ring nitrogen of formula(I); R¹ is C₂₋₄ alkenyl or C₂₋₄ alkynyl either of which is optionallysubstituted by halogen, alkoxy, cycloalkyl, phenyl (optionallysubstituted by halogen), pyridinyl (optionally substituted by halogen)or cyano; or an acid addition salt, quaternary ammonium salt or N-oxidederived thereform.
 2. A compound of formula (I) as claimed in claim 1wherein Ar is pyridinyl optionally substituted with halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₂₋₄ alkynyl or cyano.
 3. A compound of formula (I) asclaimed in claim 1 wherein R is C₁₋₄ alkyl, C₂₋₄ haloalkyl (the α-carbonbeing unsubstituted) or C₁₋₄ alkoxycarbonyl.
 4. An insecticidal,acaricidal or nematicidal composition comprising a pesticidallyeffective amount of a compound of formula (I) as claimed in claim 1 anda suitable carrier or diluent therefor.
 5. A method of combating andcontrolling insect, acarine or nematode pests at a locus which comprisestreating the pests or the locus of the pests with pesticidally effectiveamount of a compound according to claim
 1. 6. A method according toclaim 5 wherein the pests are insect pests of growing plants.
 7. Amethod of combating and controlling insect, acarine or nematode pests ata locus which comprises treating the pests or the locus of the pestswith a pesticidally effective amount of a composition according to claim5.